Crystals solid formulations

The significance of this novel attempt lies in the inclusion of both the additional particle co-ordinate and in a mechanism of particle disruption by primary particle attrition in the population balance. This formulation permits prediction of secondary particle characteristics, e.g. specific surface area expressed as surface area per unit volume or mass of crystal solid (i.e. m /m or m /kg). It can also account for the formation of bimodal particle size distributions, as are observed in many precipitation processes, for which special forms of size-dependent aggregation kernels have been proposed previously. 

The amorphous phase is not usually a desirable state for the API because the formation process is more random and difficult to control than a crystallization. A second dispersed liquid phase is usually formed just prior to freezing and may coalesce or disperse under the influence of hydrodynamic forces in the crystallizer, making the process sensitive to micro-mixing effects on scale up. Amorphous solids also have significantly lower thermodynamic stability than related crystalline material and may subsequently crystallize during formulation and storage. Because of the non-uniformity of the amorphous solid it can more easily incorporate molecules other than the API, making purification less effective. 

Solid formulations for sustained drug release may contain mesogenic polymers as excipients. The mesogenic polymers form a matrix, which is usually compressed into tablets. Some of the most frequently used excipients for sustained release matrices include cellulose derivatives, which behave like lyotropic liquid crystals when they are gradually dissolved in aqueous media. Cellulose derivatives such as hydroxy-propyl cellulose or hydroxy-propylmethyl cellulose form gel-like lyotropic mesophases in contact with water, through which diffusion takes place relatively slowly. Increasing dilution of the mesophase with water transforms the mesophase to a highly viscous slime and then to a colloidal polymer solution. 

A dramatic example of the impact of crystal polymorphism on a drug formulation is that of ritonavir (Norvir ), used for the treatment of HIV patients. The problem arose in May of 1998, approximately two years after the launch of the drug, when researchers at the Abbott Laboratories became aware that after 240 production batches it was no longer possible to obtain ritonavir in the crystal form (Form I) approved by the FDA and required for the formulation of Norvir because of the sudden and unexpected appearance of a more stable and much less soluble crystal form (Form II, Fig. 3.3.17). The loss of control over the production process forced Abbott to withdraw the drug from the market for approximately one year until they learned how to replace the solid formulation with a gel capsule suspension with greater problems of stability and bioavailability. Subsequent investigations have led to the discovery of four other crystalline forms of ritonavir [33]. 

Tetranitropropane diurea is a white crystal solid with a density of 1.93 g/cm. This compound exhibits better hydrolytic stability than similar compounds. It is stable in neutral and acidic medium while immediate decomposition was observed in alkaline medium (0.1 M NaOH). The compound was further characterized for its preliminary explosive properties (Table 1). The results show that the compound itself is sensitive to both impact and fiiction but it has high thermal stability. TNPDU has a relatively small particle size of 32 pm with a typical broad distribution and exhibits often two distinct modes. The size meets the requirements for propellant and explosive formulations. 

Larsen G, Skotak M (2008) Co-solvent mediated fiber diameter and fiber morphology control in electrospinning of sol-gel formulations. J Non Crystal Solids 354 5547-5554... 

The state of the surface is now best considered in terms of distribution of site energies, each of the minima of the kind indicated in Fig. 1.7 being regarded as an adsorption site. The distribution function is defined as the number of sites for which the interaction potential lies between and (rpo + d o)> various forms of this function have been proposed from time to time. One might expect the form ofto fio derivable from measurements of the change in the heat of adsorption with the amount adsorbed. In practice the situation is complicated by the interaction of the adsorbed molecules with each other to an extent depending on their mean distance of separation, and also by the fact that the exact proportion of the different crystal faces exposed is usually unknown. It is rarely possible, therefore, to formulate the distribution function for a given solid except very approximately. 

A new class of solvents called ionic liquids has been developed to meet this need. A typical ionic liquid has a relatively small anion, such as BF4, and a relatively large, organic cation, such as l-butyl-3-methylimidazolium (16). Because the cation has a large nonpolar region and is often asymmetrical, the compound does not crystallize easily and so is liquid at room temperature. However, the attractions between the ions reduces the vapor pressure to about the same as that of an ionic solid, thereby reducing air pollution. Because different cations and anions can be used, solvents can be designed for specific uses. For example, one formulation can dissolve the rubber in old tires so that it can be recycled. Other solvents can be used to extract radioactive waste from groundwater. 

Bixbyite, found only in Utah, about 35 miles southwest of Simpson, is described by Penfield and Foote2) as forming shiny black cubic crystals with a trace of octahedral cleavage. The composition assigned it by them was Fe++Mn+40A, with a little isomorphous replacement of Fe++ by Mg++ and Mn++ and of Mn+i by Ti+i. It was shown by Zachariasen that the X-ray data exclude this formulation, and indicate instead that the mineral is a solid solution of Mn20A and Fe20A. We shall reach a similar conclusion. 

To reach W = 1 and S = 0, we must remove as much of this vibrational motion as possible. Recall that temperature is a measure of the amount of thermal energy in a sample, which for a solid is the energy of the atoms or molecules vibrating in their cages. Thermal energy reaches a minimum when T = 0 K. At this temperature, there is only one way to describe the system, so — 1 and — 0. This is formulated as the third law of thermodynamics, which states that a pure, perfect crystal at 0 K has zero entropy. We can state the third law as an equation, Equation perfect crystal T=0 K) 0... 

The growth of lactose crystals in ice cream results in a serious texture defect known as sandiness. It is usually caused by temperature fluctuations, high serum solids in the mix, and high cabinet storage temperatures. The ratio of serum solids and moisture must be controlled. Hydrocolloids have some effect on controlling sandiness, but not as much as proper handling techniques and formulation. 

The phenomenon of pseudopolymorphism is also observed, i.e., compounds can crystallize with one or more molecules of solvent in the crystal lattice. Conversion from solvated to nonsolvated, or hydrate to anhydrous, and vice versa, can lead to changes in solid-state properties. For example, a moisture-mediated phase transformation of carbamazepine to the dihydrate has been reported to be responsible for whisker growth on the surface of tablets. The effect can be retarded by the inclusion of Polyoxamer 184 in the tablet formulation [61]. 

Some tablets combine sustained-release and rapid disintegration characteristics. Products such as K-Dur (Key Pharmaceuticals) combine coated potassium chloride crystals in a rapidly releasing tablet. In this particular instance, the crystals are coated with ethylcellulose, a water-insoluble polymer, and are then incorporated into a rapidly disintegrating microcrystalline cellulose (MCC) matrix. The purpose of this tablet is to minimize GI ulceration, commonly encountered by patients treated with potassium chloride. This simple but elegant formulation is an example of a solid dosage form strategy used to achieve clinical goals. 

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